IgA nephropathy is characterized by mesangial cell proliferation and extracellular matrix expansion associated with immune deposits consisting of galactose-deficient polymeric IgA1 and C3. We have previously shown that IgA-binding regions of streptococcal M proteins co-localize with IgA in mesangial immune deposits in patients with IgA nephropathy. In the current study, the IgA-binding M4 protein from group A streptococcus was found to bind to galactose-deficient polymeric IgA1 with higher affinity than to other forms of IgA1, as shown by surface plasmon resonance and solid-phase immunoassay. The M4 protein was demonstrated to bind to mesangial cells not via the IgA-binding region but rather via the C-terminal region, as demonstrated by flow cytometry. IgA1 enhanced binding of M4 to mesangial cells, but not vice versa. Co-stimulation of human mesangial cells with M4 and galactose-deficient polymeric IgA1 resulted in a significant increase in IL-6 secretion compared to each stimulant alone. Galactose-deficient polymeric IgA1 alone, but not M4, induced C3 secretion from the cells and co-stimulation enhanced this effect. In addition, co-stimulation enhanced mesangial cell proliferation compared to each stimulant alone. These results indicate that IgA-binding M4 protein binds preferentially to galactose-deficient polymeric IgA1 and that these proteins together induce excessive pro-inflammatory responses and proliferation of human mesangial cells. Thus, tissue deposition of streptococcal IgA-binding M proteins may contribute to the pathogenesis of IgA nephropathy.
IgA nephropathy (IgAN) and Henoch-Schönlein purpura (HSP) are diseases characterized by IgA deposits in the kidney and/or skin. Both may arise after upper respiratory tract infections, but the pathogenic mechanisms governing these diseases remain unclear. Patients with IgAN (n = 16) and HSP (n = 17) were included in this study aimed at examining whether IgA-binding M proteins of group A streptococci could be involved. As M proteins vary in sequence, the study focused on the IgA-binding-region (IgA-BR) of three different M proteins: M4, M22, and M60. Renal tissue from IgAN and HSP patients and skin from HSP patients were examined for deposits of streptococcal IgA-BR by immunohistochemistry and electron microscopy using specific antibodies, and a skin sample from a HSP patient was examined by mass spectrometry. IgA-BR deposits were detected in 10/16 IgAN kidneys and 7/13 HSP kidneys. Electron microscopy demonstrated deposits of IgA-BRs in the mesangial matrix and glomerular basement membrane, which colocalized with IgA. Skin samples exhibited IgA-BR deposits in 4/5 biopsies, a result confirmed by mass spectrometry in one patient. IgA-BR deposits were not detected in normal kidney and skin samples. Taken together, these results demonstrate IgA-BR from streptococcal M proteins in patient tissues. IgA-BR, would on gaining access to the circulation, encounter circulatory IgA and form a complex with IgA-Fc that could deposit in tissues and contribute to the pathogenesis of IgAN and HSP.
28Most patients with IgA nephropathy exhibit complement deposition in the glomerular 29 mesangium. Certain cases of IgA nephropathy have been associated with reduced levels of 30 factor H. A recent study could not demonstrate mutations at the C terminal of factor H. We 31 describe a novel heterozygous mutation in factor H, position A48S (nucleotide position 142 32 G>T, alanine>serine), detected in exon 2 of a 14 year old girl with IgA nephropathy. The 33 patient exhibited reduced levels of C3 and factor H, the latter suggesting that the mutation 34 affected factor H secretion. The patient developed initial signs and symptoms of 35 glomerulonephritis at the age of 9 years but presented again at the age of 14 years with weight 36 gain, renal failure, nephrotic-range proteinuria and malignant hypertension.
Antibody levels to the IgA-BRs were significantly higher in IgAN patients than controls (P = 0.016), particularly in patients with recent streptococcal infection (P = 0.008). Conclusions. The results suggest that children with IgAN had a previous infection with a streptococcal strain expressing an IgA-binding M protein.
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